PM01183 (lurbinectedin) is a new anticancer drug that blocks trans-activated transcription, induces DNA double-strand breaks and modulates the tumor microenvironment. PM01183 activity has been observed in different tumor types, and in patients resistant to platinum-based chemotherapy (CT). The activity observed against homologous-recombination-deficient cell lines prompted a phase II trial in metastatic breast cancer (MBC) patients (pts) with deleterious germline BRCA mutations (BRCA+).
BRCA+ MBC pts pretreated with ≤ 3 CT regimens in the advanced/metastatic setting, measurable disease per RECIST v1.1, performance status (PS) ≤ 1, and adequate major organ function were treated with PM01183 IV q3wk. A protocol amendment adjusted the starting dose from 7 mg fixed dose (FD) to 3.5 mg/m2 to improve safety. Primary endpoint was overall response rate (ORR) by RECIST v1.1 with further development of PM01183 if ≥ 17 responses of 53 evaluable pts were confirmed.
As of May 2016, 54 eligible pts (median age 43 years, median 1 prior advanced CT) have been treated (35 with 7 mg FD; 19 with 3.5 mg/m2). PS 0: 30 pts; prior anthracyclines: 45 pts, taxanes: 47 pts, platinum: 27 pts, PARP inhibitors: 9 pts; >2 metastatic sites: 33; BRCA 1: 30 pts; triple negative: 31 pts.
|Median cycles (range)||4 (1–24)|
|Best overall response||n = 51 evaluable|
|ORR (95%CI)||39% (26–54) 37 / 44% (7 mg FD / 3.5 mg/m2)|
|- Platinum pretreated||23% (9–44)|
|Median duration of response months (95%CI)||4.6 (3.4–11.3)|
|Progression-free survival months (95%CI)||4.1+ (2.6–6.0)|
Most common grade (G) 3–4 related adverse events (7 mg FD / 3.5 mg/m2) were (%): neutropenia 71 / 50 (G4: 51/6); febrile neutropenia 29 / 6; thrombocytopenia 26 / 6 (G4; 20/0); G3 fatigue 17 / 17; transaminase increase 26 / 11 (G4; 3/0); and G3 nausea 9 / 6.
Primary endpoint was met. PM01183 is an active drug in BRCA+ MBC, regardless of prior platinum treatment. At 3.5 mg/m2, the tolerance improved notably, while maintaining the efficacy. Further development is warranted in this indication and a Phase 3 trial is planned.
Clinical trial identification
Legal entity responsible for the study
J. Balmaña: Receipt of grants / research supports; PharmaMar. Paticipation in a company sponsored speaker's bureau; AstraZeneca.
C.M. Fernandez: PharmaMar employee. C. Kahatt, S. Szyldergemajn, A. Soto-Matos: PharmaMar employee and stock ownership. A. Perez de la Haza: PharmaMar employee. All other authors have declared no conflicts of interest.